NM_001088.3:c.468C>T

Variant names:

• chr17-76469814-C-T
• rs2071031
• NM_001088.3:c.468C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001088.3(AANAT):​c.468C>T​(p.Ala156Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,604,098 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (38 hom.)
• Consequence: AANAT NM_001088.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.04
• Publications: 2 publications found

Genes affected

AANAT (HGNC:19): (aralkylamine N-acetyltransferase) The protein encoded by this gene belongs to the acetyltransferase superfamily. It is the penultimate enzyme in melatonin synthesis and controls the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for the function of the circadian clock that influences activity and sleep. This enzyme is regulated by cAMP-dependent phosphorylation that promotes its interaction with 14-3-3 proteins and thus protects the enzyme against proteasomal degradation. This gene may contribute to numerous genetic diseases such as delayed sleep phase syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-76469814-C-T is Benign according to our data. Variant chr17-76469814-C-T is described in ClinVar as Benign. ClinVar VariationId is 714416.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00181 (2632/1451750) while in subpopulation EAS AF = 0.0305 (1198/39244). AF 95% confidence interval is 0.0291. There are 38 homozygotes in GnomAdExome4. There are 1299 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001088.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AANAT	NM_001088.3	MANE Select	c.468C>T	p.Ala156Ala	synonymous	Exon 4 of 4	NP_001079.1	F1T0I5
	AANAT	NM_001166579.2		c.603C>T	p.Ala201Ala	synonymous	Exon 7 of 7	NP_001160051.1	Q16613-2
	AANAT	NR_110548.2		n.724C>T		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AANAT	ENST00000392492.8	TSL:1 MANE Select	c.468C>T	p.Ala156Ala	synonymous	Exon 4 of 4	ENSP00000376282.2	Q16613-1
	AANAT	ENST00000250615.7	TSL:1	c.603C>T	p.Ala201Ala	synonymous	Exon 7 of 7	ENSP00000250615.2	Q16613-2
	AANAT	ENST00000878873.1		c.468C>T	p.Ala156Ala	synonymous	Exon 4 of 4	ENSP00000548932.1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152230 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00326 AC: 748 AN: 229192 AF XY: 0.00305

Gnomad AFR exome AF: 0.0000720

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.000420

Gnomad EAS exome AF: 0.0165

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.00372

GnomAD4 exome AF: 0.00181 AC: 2632 AN: 1451750 Hom.: 38 Cov.: 31 AF XY: 0.00180 AC XY: 1299 AN XY: 721430

African (AFR) AF: 0.0000901 AC: 3 AN: 33310

American (AMR) AF: 0.0000229 AC: 1 AN: 43676

Ashkenazi Jewish (ASJ) AF: 0.000387 AC: 10 AN: 25862

East Asian (EAS) AF: 0.0305 AC: 1198 AN: 39244

South Asian (SAS) AF: 0.000791 AC: 67 AN: 84676

European-Finnish (FIN) AF: 0.0189 AC: 970 AN: 51360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5258

European-Non Finnish (NFE) AF: 0.000236 AC: 262 AN: 1108454

Other (OTH) AF: 0.00202 AC: 121 AN: 59910

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152348 Hom.: 2 Cov.: 32 AF XY: 0.00303 AC XY: 226 AN XY: 74500

African (AFR) AF: 0.0000722 AC: 3 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.0175 AC: 91 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0175 AC: 186 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.000778

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.34
DANN	Benign	0.91
PhyloP100		-2.0
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2071031; hg19: chr17-74465896;